Background

The national incidence of and risk factors for hospitalized avascular necrosis (AVN) in renal transplant recipients has not been reported.

Methods

This historical cohort study consisted of 42,096 renal transplant recipients enrolled in the United States Renal Data System (USRDS) between 1 July 1994 and 30 June 1998. The data source was USRDS files through May 2000. Associations with hospitalizations for a primary diagnosis of AVN (ICD-9 codes 733.4x) within three years after renal transplant were assessed in an intention-to-treat design by Cox regression analysis.

Results

Recipients had a cumulative incidence of 7.1 episodes/1000 person-years from 1994 to 1998. The two-year incidence of AVN did not change significantly over time. Eighty-nine percent of the cases of AVN were due to AVN of the hip (733.42) and 60.2% of patients with AVN underwent total hip arthroplasty (THA); these percentages did not change significantly over time. In the Cox regression analysis, an earlier year of transplant, African American race [adjusted hazard ratio (AHR), 1.65, 95% confidence interval (CI) 1.33 to 2.03], allograft rejection (AHR 1.67, 95% CI 1.35 to 2.07), peritoneal dialysis (vs. hemodialysis; AHR 1.44, 95% CI 1.15 to 1.81), and diabetes (AHR 0.41, 95% CI 0.27 to 0.64) were the only factors independently associated with hospitalizations for AVN.

Conclusions

The incidence of AVN did not decline significantly over time in the renal transplant population. Patients with allograft rejection, African American race, peritoneal dialysis and earlier date of transplant were at the highest risk of AVN, while diabetic recipients were at a decreased risk.

METHODS

Patient population

This study examined data from the USRDS, using standard analysis files (SAFs) as of May 2000. The USRDS, indirectly mandated by federal law, incorporates baseline and follow-up demographic and clinical data on all patients receiving ESRD therapy in the United States. ESRD therapy includes hemodialysis, peritoneal dialysis, and renal transplantation. Because patient entry into the USRDS is linked to Medicare reimbursement, and ESRD services are expensive, very few transplant patients are not represented in the database. The variables included in the USRDS SAFs as well as data collection methods and validation studies are listed at the USRDS website (under "Researcher's Guide to the USRDS Database," Section E, "Contents of all the SAF's,"http://www.usrds.org) and published in the USRDS. The demographics of the renal transplant population have been previously described (2001 USRDS report). SAF.TXUNOS was used as the primary dataset, and merged with variables from SAF.HOSP for hospitalization data, and SAF.PATIENTS for dates and causes of death as well as causes of renal disease, as previously reported^7,8,9. Patient characteristics and treatment factors were those at the date of transplant. Recipients of organs other than kidneys were excluded.

Outcome definition

This historical cohort study was conducted to examine the incidence, risk factors and associated patient survival for hospitalized cases of AVN [based on International Classification of Diseases-9th Modification Diagnosis Codes (ICD9) at hospital discharge for AVN, 733.4x, excluding avascular necrosis due to malignancy] as a primary discharge diagnosis in renal transplant recipients. The first hospitalization for AVN after the first renal transplant for a given individual occurring on or after July 1, 1994 and before July 1, 1998, with follow-up time truncated at three years was counted in the analysis. Hospitalizations were chosen because they were more accessible in the database and less subject to interpretation than outpatient cases of AVN, especially since the USRDS database has no information on confirmatory studies. Hospitalization data for transplant recipients may be unreliable after the patient has survived 3 years post-transplant, when hospitalization reporting to Medicare for patients 65 years or younger is no longer required. However, Medicare reporting starts immediately after transplant, regardless of the preceding dialysis status. All hospitalizations with a primary discharge diagnosis for AVN were extracted from SAF.HOSP, merged with the transplant file using unique identifiers, and hospitalizations outside the range of the study period were excluded. Hospitalizations for AVN occurring at any time after renal transplant, including after graft failure (censored for patient death), were counted in the analysis.

Variables used in the analysis

The independent associations between patient factors and hospitalizations for AVN were examined using multivariate analysis with stepwise analysis including recipient and donor age, recipient race, gender, weight, pretransplant dialysis (yes/no), duration of dialysis prior to transplantation, total follow-up time, repeat transplant, donor cytomegalovirus serology, dialysis in the first week after transplant (delayed graft function, yes/no), rejection (either treatment or diagnosis) occurring at any time in the study period, induction antibody therapy, maintenance immunosuppressive medications at time of discharge after transplant surgery, graft loss, and cause of ESRD (diabetes, systemic lupus erythematosus). Episodes of rejection were not restricted to those occurring in the first year, in contrast to studies of allograft function, since there is no evidence that late (vs. early) rejection has a different impact on AVN. The total cumulative dose of prednisone was not available in the USRDS. UNOS tracks the numbers of days of prednisone administered prior to initial hospital discharge; however, values were missing for>90% of patients in both databases and could not be used as a covariate in the above analyses. The use of maintenance immunosuppressive medication at the time of discharge after transplantation also was analyzed as a preexisting covariate. Information on use of medications (other than immunosuppressive medications), alcohol, tobacco, or radiologic procedures was not available. Dialysis modality was obtained from the file SAF.RXHIST60. The initial dialysis modality a patient used for at least 60 days after presentation to ESRD was utilized in an intention-to-treat fashion.

Survival times

To determine the time to AVN value, survival time was defined as the time from first renal transplant until hospitalization for AVN, with patients censored at death, loss to follow-up, or end of the study. The patient survival probabilities were estimated by using the Kaplan Meier method.

Statistical analysis

All analyses were performed using SPSS 9.0 TM (SPSS, Inc., Chicago, IL, USA). Files were merged and converted to SPSS files using DBMS/Copy (Conceptual Software, Houston, TX, USA). Univariate analysis was performed with Chi-square testing for categorical variables and Student's two-sided t test for continuous variables. Variables with P < 0.10 in univariate analysis for a relationship with the development of hospitalization for AVN were entered into multivariate analysis as covariates. Life table analyses were used to calculate two-year incidences of AVN by year of transplantation. Kaplan-Meier analysis was used to construct survival plots of time to hospitalized AVN after renal transplantation. Stepwise Cox regression (likelihood ratio method) was used to model factors associated with time to hospitalized AVN, controlling for covariates listed above.

RESULTS

There were 42,096 solitary renal transplant recipients in the United States Renal Data System transplanted from July 1, 1994 to June 30, 1998. Of these, 563 recipients were hospitalized with a primary discharge diagnosis of AVN, with 645 total hospitalizations. The incidence of hospitalized AVN in renal transplant recipients was 7.1 episodes/1000 patient-years. The most recent hospitalization date was December 28, 1999. The most recent date of death was April 2000. Twenty-seven patients had hospitalized AVN after graft loss. Of recipients hospitalized for AVN, 89% had AVN of the hip, 5.0% had AVN site unspecified, 2.7% had AVN of the humerus, 2.1% had AVN of the femoral condyle, and 0.9% had AVN of the talus. Of the recipients hospitalized for AVN, 60.2% (339) underwent total hip arthroplasty (THA), and another 6.9% underwent some type of hip arthroplasty. Of the patients hospitalized for AVN who did not undergo THA, 19.5% underwent bone excision of the femur, and 14.1% underwent bone grafting to the femur. The two-year incidence of AVN, along with the proportion of patients hospitalized for AVN who underwent THA (also within 2 years of transplant), is shown in Figure 1. There was no significant change in the incidence of AVN or the proportion of patients with AVN who underwent THA over time. The time to hospitalization for AVN is shown in Figure 2, which depicts a low rate of hospitalized AVN the first year after transplantation, and a steady increase afterward, even after two years.

Figure 1.

Two-year incidence of hospitalized avascular necrosis (AVN) after renal transplantation (per 100,000 patient-years), by year of renal transplantation (). The right column () represents the proportion of patients hospitalized for AVN who underwent total hip replacement (THR, also within two years post-transplant). Neither the incidence of AVN nor the proportion of patients with AVN who underwent THR changed significantly over time.

Full figure and legend (24K)

Figure 2.

Time to hospitalization for AVN, U.S. renal transplant recipients from July 1, 1994 to 1998. N = 42,096 patients, with a follow-up period truncated at three years post-transplant. The proportion of patients who experienced AVN in the first post-transplant year was 0.26%, compared with 0.83% in the second post-transplant year and 0.84% in the third post-transplant year. As shown, in contrast to prior studies, the risk of AVN was actually lowest in the first transplant year and increased at a similar rate the remaining two years. This may reflect the preferred timing of total hip replacement, which is the definitive therapy for AVN.

Full figure and legend (13K)

Continuous variables in patients hospitalized for AVN vs. all other renal transplant recipients is shown in Table 1. Only body mass index and duration of follow-up differed significantly by AVN status.

Table 1 - Continuous variables associated with hospitalized avascular necrosis in renal transplant recipients hospitalized for avascular necrosis (AVN) versus all other renal transplant recipients, July 1, 1994–June 30, 1998.

Full table

In univariate analysis Table 2, recipient African American race, recipient weight, diabetes, hypertension and glomerulonephritis as causes of ESRD, peritoneal dialysis (vs. hemodialysis) and donor type were significantly different between recipients hospitalized for AVN versus all other recipients. Recipients with hospitalized AVN were older than other recipients. The number of days of prednisone use prior to discharge was analyzed as a categorical variable by quartiles, but still had no significant association with hospitalized AVN. When patients who underwent THA were excluded from analysis, all of the associations in this paragraph, including that with diabetes, persisted.

Table 2 - Categorical variables of renal transplant recipients hospitalized for avascular necrosis (AVN) versus all other renal transplant recipients, July 1, 1994–June 30, 1998^, .

Full table

In multivariate analysis with hospitalization for AVN after transplantation as the outcome variable, significant associations were found with earlier year of transplant, African American race, rejection, peritoneal dialysis, and ESRD due to diabetes Table 2. There were no significant interactions between covariates, specifically no interactions between maintenance or induction medications. Body mass index (BMI) was not significant either as a continuous or categorical variable.

DISCUSSION

The present study of a national renal transplant population confirms the widely held impression that hospitalized AVN is becoming less frequent in renal transplant recipients^10,11,12. All patients in the study had the potential for at least 20 months of follow-up. Although we were unable to capture cases of AVN managed on an outpatient basis, the consistent ratio of patients hospitalized for AVN who underwent THA Figure 1 indicates that the declining incidence of hospitalized AVN was not merely due to differences in hospital utilization, since the primary reason for hospitalization of patients with AVN appeared to be for THA. Perhaps the most striking finding of the study is that, as a hospitalized diagnosis after renal transplantation, avascular necrosis (7.1/1000 person-years) was nearly as common as all causes of hospitalized fractures combined (7.2/1000 person-years) using the same patient population¹³. Reports on the natural history of hospitalized AVN after renal transplantation are few, but those available indicate that conservative therapy suffices for 40% of cases of AVN of the hip¹⁴. This is similar to the findings of the present study. In contrast to frequent reports that 80% of patients with AVN become symptomatic within two years post transplant¹⁵, Figure 2 indicates that the risk of hospitalized AVN from two to three years after transplant is essentially the same as the risk from one to two years. The apparent low risk for hospitalized AVN within one year after transplant may reflect caution on the part of transplant providers in attempting to avoid THA, a major elective surgery, in the first transplant year (when steroid dosing is usually higher and may impair wound healing), rather than the time at which patients develop symptoms. We were unable to assess cases in which intraosseous plethysmography and venography for core decompression¹⁶ were performed, as these were not coded by ICD9 procedure codes, and may be performed as outpatient therapy. However, bone excision and bone grafting could be assessed. Although these procedures also presumably would require hospitalization, they were much less common as hospitalized procedures for AVN than THA.

Many studies relate the development of hospitalized AVN to the use of corticosteroids. Because of limitations of the USRDS database, there was no information on the cumulative steroid dosages patients received. We were thus unable to construct a "dose-response" curve to determine a threshold cumulative dose of prednisone and the development of hospitalized AVN, which would have been clinically useful. However, no previous study of AVN—whether in renal transplantation or in patients with systemic lupus erythematosus—has clearly shown a "threshold" cumulative dose associated with AVN. Although many studies have identified corticosteroids as a risk factor for AVN, most were small and retrospective, without controls, and were conducted in patients with systemic lupus erythematosus (SLE)¹⁷. Comparison between studies of AVN in patients with SLE also may be confounded by pre-existing bone disease in most transplant recipients. Whether hyperparathyroid or adynamic bone disease contributes to the risk of AVN has not been confirmed. The largest previous study of AVN in renal transplantation was by Fryer et al, who studied 748 adult kidney transplant recipients with at least one year of follow-up¹⁸. In that cohort, 5.5% of recipients developed AVN (mean follow-up and incidence not given). However, while the duration of steroid use was independently associated with all bone related complications, it was not independently associated with the risk of AVN. Furthermore, the overall rate of hospitalized AVN in patients taking corticosteroids is still low. The Hopkins Lupus Cohort Trial found that each two-month exposure to high-dose (>1 mg/kg/day) prednisone, but not the total cumulative prednisone dose or individual pulse doses of prednisone, increased the risk of AVN in lupus patients¹⁹. In a case control study of 42 patients with systemic lupus erythematosus, 17 of whom developed AVN versus 25 who did not, the patients who developed AVN had received higher doses of corticosteroids in the first one, three and six months of therapy²⁰. Neither the duration of therapy nor the total dose of corticosteroids differed between groups.

The significance of rejection, which has been a risk factor for post-transplant AVN in prior studies²¹, may represent recipients who received substantially higher cumulative doses of corticosteroids, since although recipients are usually tapered to approximately 10 mg per day of prednisone within the first few months of transplant, those who experience rejection are often "recycled" (restarted on higher oral doses of corticosteroids and continued for a longer time) in addition to pulse corticosteroid therapy²². The significance of African American race may represent the inability of the present study to account for cumulative doses of corticosteroids, since African Americans usually receive higher cumulative doses of immunosuppression due to their poorer HLA matching and sensitization leading to higher risk of graft loss²³. African American race has been cited as a risk factor for AVN in the transplanted¹¹ and general populations, although the strong association of African American race with SLE probably confounds this observation. AVN has been infrequently reported in patients with sickle cell trait²⁴, while sickle cell disease is a known risk factor for AVN²⁵. Although it is possible that the sickle cell trait and corticosteroid treatment might be synergistic for the risk of AVN, studies of patients with SLE have not identified race as an independent risk factor for AVN when the total dose of corticosteroids was taken into account²⁶.

Recent reports indicate that 3-hydroxy-3-methlyglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may reduce the risk of osteonecrosis in patients receiving corticosteroid therapy²⁷. Statins also increase bone mineral density and reduce the risk of osteoporotic fractures²⁸, although the relevance of this mechanism to AVN is controversial. Although we were unable to determine use of statins in our population, statin use is increasing in the ESRD population²⁹. The role of hyperlipidemia in AVN also has been suggested by studies in patients with Gaucher disease³⁰, and the connection between hyperlipidemia and AVN after renal transplantation needs to be explored in future studies.

Diabetes has not been studied in analysis of risk for AVN in previous studies. Since 63% of recipients hospitalized for AVN underwent total hip arthroplasty, hospitalization was most commonly employed for definitive procedures in this condition. Diabetes is a known risk factor for infection^31,32 and cardiovascular disease^33,34 after renal transplantation. Therefore, diabetic patients may succumb from other causes and not live long enough to develop AVN or other indications for THA after renal transplantation, or diabetic candidates may be considered poor candidates for THA. Another possible explanation is that diabetic patients may have more rapid tapering of corticosteroids doses and thus less cumulative steroid exposure after transplantation³⁵. In contrast to diabetes as a cause of renal disease, post-transplant diabetes has been associated with a high risk of AVN³⁶. However, we were unable to assess for the new development of diabetes after transplantation in the USRDS database. Diabetes also has an association with adynamic bone disease prior to transplantation³⁷. The present study results showed an association between AVN and a prior history of peritoneal dialysis, which also has an association with adynamic bone disease³⁸. Adynamic bone disease also has a strong negative association with African American race³⁹. The negative association between diabetes and Caucasian race with AVN in the present analysis is intriguing but cannot be fully explained by the database.

There are several limitations to this retrospective study. Findings are associative, not causative, and risk cannot be assigned without the ability to control for other variables prospectively during the course of the study. This study could not independently verify radiological findings. We could not assess use of alcohol or other risk factors associated with hospitalized AVN⁴⁰. However, ICD-9 coding for determining rates of medical conditions has been used in other published studies,^{41,42,43,44,45,46} as well as the National Center for Health Statistics (http://www.cdc.gov/nchs). Another reason for underestimating the frequency of AVN in this population would be the current study's limitation to hospitalized cases of AVN. Therefore, recipients hospitalized for AVN were compared to recipients not hospitalized for AVN in this analysis, perhaps also accounting for the lack of significance of certain factors. Nevertheless, hospitalized AVN would be a marker for more severe and disabling AVN. This was borne out by the high rate of THA among recipients with hospitalized AVN in this study, and is comparable to the high rate of surgical intervention in non-transplant patients with AVN⁴⁷. As indicated previously, however, the rate of hip replacement in patients hospitalized for AVN did not change over time. There is no evidence that renal transplant recipients preferentially receive inpatient management for AVN compared to the general population. The short follow-up duration of the study may be a limitation also, although previous studies have demonstrated the peak risk for AVN occurs within two years post-transplant¹⁵. Strengths of the present analysis include its large size and population-based character, and relatively complete capture and follow-up.

The present study confirms that hospitalization for AVN can be associated with significant morbidity, especially given the high rate of THA in this analysis. It has been difficult to establish screening or preventive measures for this complication. In fact, the only available preventive strategy has been tapering presumed "high risk" patients off steroids or down to a minimal dose as quickly as possible. Investigation into the pathogenesis and potential therapy for this condition would require an experimental model, which is currently lacking. There have been no trials of statins for the prevention of AVN in renal transplantation, and other than "high" steroid dose, there is no general agreement on which transplant recipients are at the most risk of AVN. The conduct of human studies would require detailed information on prevalence, incidence, and risk factors for hospitalized AVN, which the present analysis provides.

References

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Acknowledgments

The opinions expressed are solely those of the authors and do not represent an endorsement by the Department of Defense or the National Institutes of Health. A portion of this study was presented as a poster at AST 2000 in Chicago, Illinois.